Imagine the possibilities

I’m going to take a break from writing about terrible phage therapy papers. Frankly, they are all very much alike, as the same errors get repeated over and over. It’s depressing for me to write these posts and I suspect it is getting to be a bit boring for you to read them.

So let’s talk about what could be happening with phage therapy: where are there genuine and immediate (at least by the standard of drug development) opportunities to improve human health and well-being? I know it’s more fun to think about really big problems like solving the antibiotic resistance crisis, or taming sepsis. But these big problems are also really hard problems that a lot of smart people with lots of resources have failed to solve for quite some time now. Let’s not forget about these problems, but consider solving a few smaller, more tractable problems now that might provide some learnings which help us solve the big problems later.

So what sorts of problems might be amenable to phage therapy? Here are a few general principles:

1. Indications where antibiotics are ineffective. This includes antibiotic resistant infections, obviously. But it also includes indications where antibiotics aren’t all that effective even in the absence of resistance. Topical infections are one example.
2. Indications where antibiotics can be counter-productive. This category includes what we might think of as microbiomic diseases – where the disruption in microbial communities caused by antibiotics leads to a high rate of relapse or increased risk of other disease.
3. Indications where delivery is easy and clearance rates are low. Phage are rapidly cleared from the bloodstream (although, as one review puts it “data are scarce”). Solving the clearance problem will be hard. I was once given the task of solving the clearance problem for RNA therapeutics. I failed. But that was 25 years ago and no one else has solved it either. There are plenty of other problems that need to be worked out in phage therapy–let’s not make solving the hardest one of all a precondition for progress.
4. Indications where just one or two bacterial species need to be targeted. Phage tend to be narrow-spectrum agents, and so you want to ID the infecting bacteria before prescribing PT. Although rapid molecular techniques exist for bacterial ID, they are expensive (at least in the context of infectious disease diagnostics). Culture-based methods are cheap but take 2-3 days to return results. Requiring an ID workup means that PT won’t get used for most outpatient indications. Better to focus on ones where just a few bugs are the likely culprits.

That’s probably enough constraints. You’ll notice I haven’t included a couple other plausible ones, like whether appropriate phage exist, and whether there is a large and potentially profitable market. As for the first, I assume that every bug has its phage, it’s just a matter of finding them. They are, after all, the most abundant organisms on Earth, and phage hunts make for fine undergraduate research projects. As for the second, I believe there are enough opportunities for government and NGO funded research that there is no need to promise a smirking MBA a 10-fold ROI.  Prove out a therapy in one or two indications, and it won’t be long before the VC herd mentality takes over and they are throwing money at even the most dubious propositions.

Not the problem we want to solve first.